Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death.[1][2] It typically causes more than one of the following: an itchy rash, throat or tongue swelling, shortness of breath, vomiting, lightheadedness, and low blood pressure. These symptoms typically come on over minutes to hours.[3]

Common causes include insect bites and stings, foods, and medications. Other causes include latex exposure and exercise. Additionally cases may occur without an obvious reason.[3] The mechanism involves the release of mediators from certain types of white blood cells triggered by either immunologic or non-immunologic mechanisms.[4] Diagnosis is based on the presenting symptoms and signs after exposure to a potential allergen.[3]

Worldwide, 0.05–2% of the population is estimated to experience anaphylaxis at some point in life. Rates appear to be increasing.[6] It occurs most often in young people and females.[5][7] Of people who go to a hospital with anaphylaxis in the United States about 0.3% die.[8] The term comes from the Ancient Greek: ἀνάana"against", and the Ancient Greek: φύλαξιςphylaxis"protection".[9]

Signs and symptoms

Signs and symptoms of anaphylaxis.

Anaphylaxis typically presents many different symptoms over minutes or hours[5][10] with an average onset of 5 to 30minutes if exposure is intravenous and 2hours if from eating food.[11] The most common areas affected include: skin (80–90%), respiratory (70%), gastrointestinal (30–45%), heart and vasculature (10–45%), and central nervous system (10–15%)[12] with usually two or more being involved.[6]

Respiratory

Respiratory symptoms and signs that may be present include shortness of breath, wheezes, or stridor.[1] The wheezing is typically caused by spasms of the bronchial muscles[15] while stridor is related to upper airway obstruction secondary to swelling.[14] Hoarseness, pain with swallowing, or a cough may also occur.[11]

Other

Gastrointestinal symptoms may include crampy abdominal pain, diarrhea, and vomiting.[1] There may be confusion, a loss of bladder control or pelvic pain similar to that of uterine cramps.[1][14] Dilation of blood vessels around the brain may cause headaches.[11] A feeling of anxiety or of "impending doom" has also been described.[6]

Causes

Anaphylaxis can occur in response to almost any foreign substance.[16] Common triggers include venom from insect bites or stings, foods, and medication.[7][17] Foods are the most common trigger in children and young adults while medications and insect bites and stings are more common in older adults.[6] Less common causes include: physical factors, biological agents such as semen, latex, hormonal changes, food additives such as monosodium glutamate and food colors, and topical medications.[14] Physical factors such as exercise (known as exercise-induced anaphylaxis) or temperature (either hot or cold) may also act as triggers through their direct effects on mast cells.[6][18] Events caused by exercise are frequently associated with the ingestion of certain foods.[11] During anesthesia, neuromuscular blocking agents, antibiotics, and latex are the most common causes.[19] The cause remains unknown in 32–50% of cases, referred to as "idiopathic anaphylaxis."[20] Six vaccines (MMR, varicella, influenza, hepatitis B, tetanus, meningococcal) are recognized as a cause for anaphylaxis, and HPV may cause anaphylaxis as well.[21]

Food

Many foods can trigger anaphylaxis; this may occur upon the first known ingestion.[7] Common triggering foods vary around the world. In Western cultures, ingestion of or exposure to peanuts, wheat, nuts, certain types of seafood like shellfish, milk, and eggs are the most prevalent causes.[6][12]Sesame is common in the Middle East, while rice and chickpeas are frequently encountered as sources of anaphylaxis in Asia.[6] Severe cases are usually caused by ingesting the allergen,[7] but some people experience a severe reaction upon contact. Children can outgrow their allergies. By age 16, 80% of children with anaphylaxis to milk or eggs and 20% who experience isolated anaphylaxis to peanuts can tolerate these foods.[16]

The frequency of a reaction to an agent partly depends on the frequency of its use and partly on its intrinsic properties.[23] Anaphylaxis to penicillin or cephalosporins occurs only after it binds to proteins inside the body with some agents binding more easily than others.[11] Anaphylaxis to penicillin occurs once in every 2,000 to 10,000 courses of treatment, with death occurring in fewer than one in every 50,000 courses of treatment.[11] Anaphylaxis to aspirin and NSAIDs occurs in about one in every 50,000 persons.[11] If someone has a reaction to penicillins, his or her risk of a reaction to cephalosporins is greater but still less than one in 1,000.[11] The old radiocontrast agents caused reactions in 1% of cases, while the newer lower osmolar agents cause reactions in 0.04% of cases.[23]

Venom

Venom from stinging or biting insects such as Hymenoptera (ants, bees and wasps) or Triatominae (kissing bugs) may cause anaphylaxis in susceptible people.[5][24][25] Previous systemic reactions, which are anything more than a local reaction around the site of the sting, are a risk factor for future anaphylaxis;[26][27] however, half of fatalities have had no previous systemic reaction.[28]

Immunologic

In the immunologic mechanism, immunoglobulin E (IgE) binds to the antigen (the foreign material that provokes the allergic reaction). Antigen-bound IgE then activates FcεRI receptors on mast cells and basophils. This leads to the release of inflammatory mediators such as histamine. These mediators subsequently increase the contraction of bronchial smooth muscles, trigger vasodilation, increase the leakage of fluid from blood vessels, and cause heart muscle depression.[4][11] There is also an immunologic mechanism that does not rely on IgE, but it is not known if this occurs in humans.[4]

Non-immunologic

Non-immunologic mechanisms involve substances that directly cause the degranulation of mast cells and basophils. These include agents such as contrast medium, opioids, temperature (hot or cold), and vibration.[4][18]Sulfites may cause reactions by both immunologic and non-immunologic mechanisms.[29]

Diagnosis

Anaphylaxis is diagnosed on the basis of a person's signs and symptoms.[6] When any one of the following three occurs within minutes or hours of exposure to an allergen there is a high likelihood of anaphylaxis:[6]

Skin involvement may include: hives, itchiness or a swollen tongue among others. Respiratory difficulties may include: shortness of breath, stridor, or low oxygen levels among others. Low blood pressure is defined as a greater than 30% decrease from a person's usual blood pressure. In adults a systolic blood pressure of less than 90 mmHg is often used.[6]

During an attack, blood tests for tryptase or histamine (released from mast cells) might be useful in diagnosing anaphylaxis due to insect stings or medications. However these tests are of limited use if the cause is food or if the person has a normal blood pressure,[6] and they are not specific for the diagnosis.[16]

Classification

There are three main classifications of anaphylaxis. Anaphylactic shock is associated with systemic vasodilation that causes low blood pressure which is by definition 30% lower than the person's baseline or below standard values.[13] Biphasic anaphylaxis is the recurrence of symptoms within 1–72 hours with no further exposure to the allergen.[6] Reports of incidence vary, with some studies claiming as many as 20% of cases.[30] The recurrence typically occurs within 8 hours.[7] It is managed in the same manner as anaphylaxis.[5] Pseudoanaphylaxis or anaphylactoid reactions are a type of anaphylaxis that does not involve an allergic reaction but is due to direct mast cell degranulation.[7][31] Non-immune anaphylaxis is the current term used by the World Allergy Organization[31] with some recommending that the old terminology no longer be used.[7]

Skin testing is available to confirm penicillin allergies, but is not available for other medications.[16] Non-immune forms of anaphylaxis can only be determined by history or exposure to the allergen in question, and not by skin or blood testing.[31]

Differential diagnosis

It can sometimes be difficult to distinguish anaphylaxis from asthma, syncope, and panic attacks.[6] Asthma however typically does not entail itching or gastrointestinal symptoms, syncope presents with pallor rather than a rash, and a panic attack may have flushing but does not have hives.[6] Other conditions that may present similarly include: scrombroidosis and anisakiasis.[7]

Post-mortem findings

In a person who died from anaphylaxis, autopsy may show an "empty heart" attributed to reduced venous return from vasodilation and redistribution of intravascular volume from the central to the peripheral compartment.[32] Other signs are laryngeal edema, eosinophilia in lungs, heart and tissues, and evidence of myocardial hypoperfusion.[33] Laboratory findings could detect increased levels of serum tryptase, increase in total and specific IgE serum levels.[33]

Prevention

Avoidance of the trigger of anaphylaxis is recommended. In cases where this may not be possible, desensitization may be an option. Immunotherapy with Hymenoptera venoms is effective at desensitizing 80–90% of adults and 98% of children against allergies to bees, wasps, hornets, yellowjackets, and fire ants. Oral immunotherapy may be effective at desensitizing some people to certain food including milk, eggs, nuts and peanuts; however, adverse effects are common.[6] For example may people develop an itchy throat, cough, or lip swelling during immunotherapy.[34] Desensitization is also possible for many medications, however it is advised that most people simply avoid the agent in question. In those who react to latex it may be important to avoid cross-reactive foods such as avocados, bananas, and potatoes among others.[6]

Epinephrine

An old version of an EpiPen auto-injector

Epinephrine (adrenaline) is the primary treatment for anaphylaxis with no absolute contraindication to its use.[5] It is recommended that an epinephrine solution be given intramuscularly into the mid anterolateral thigh as soon as the diagnosis is suspected. The injection may be repeated every 5 to 15 minutes if there is insufficient response.[5] A second dose is needed in 16-35% of episodes with more than two doses rarely required.[5] The intramuscular route is preferred over subcutaneous administration because the latter may have delayed absorption.[5][36] Minor adverse effects from epinephrine include tremors, anxiety, headaches, and palpitations.[6]

People on β-blockers may be resistant to the effects of epinephrine.[7] In this situation if epinephrine is not effective intravenous glucagon can be administered which has a mechanism of action independent of β-receptors.[7]

Adjuncts

Antihistamines (both H1 and H2), while commonly used and assumed effective based on theoretical reasoning, are poorly supported by evidence. A 2007 Cochrane review did not find any good-quality studies upon which to base recommendations[38] and they are not believed to have an effect on airway edema or spasm.[7]Corticosteroids are unlikely to make a difference in the current episode of anaphylaxis, but may be used in the hope of decreasing the risk of biphasic anaphylaxis. Their prophylactic effectiveness in these situations is uncertain.[30]Nebulizedsalbutamol may be effective for bronchospasm that does not resolve with epinephrine.[7]Methylene blue has been used in those not responsive to other measures due to its presumed effect of relaxing smooth muscle.[7]

Preparedness

People prone to anaphylaxis are advised to have an "allergy action plan." Parents are advised to inform schools of their children's allergies and what to do in case of an anaphylactic emergency. The action plan usually includes use of epinephrine autoinjectors, the recommendation to wear a medical alert bracelet, and counseling on avoidance of triggers.[39]Immunotherapy is available for certain triggers to prevent future episodes of anaphylaxis. A multi-year course of subcutaneous desensitization has been found effective against stinging insects, while oral desensitization is effective for many foods.[12]

Prognosis

In those in whom the cause is known and prompt treatment is available, the prognosis is good.[40] Even if the cause is unknown, if appropriate preventative medication is available, the prognosis is generally good.[11] If death occurs, it is usually due to either respiratory (typically asphyxia) or cardiovascular causes (shock),[4][7] with 0.7–20% of cases causing death.[11][15] There have been cases of death occurring within minutes.[6] Outcomes in those with exercise-induced anaphylaxis are typically good, with fewer and less severe episodes as people get older.[20]

Epidemiology

The number of people who get anaphylaxis is 4–100 per 100,000 persons per year,[7][41] with a lifetime risk of 0.05–2%.[42] About 30% of people get more than one attack.[41]

Rates appear to be increasing: with the numbers in the 1980s being approximately 20 per 100,000 per year, while in the 1990s it was 50 per 100,000 per year.[12] The increase appears to be primarily for food-induced anaphylaxis.[43] The risk is greatest in young people and females.[5]>[7]

Currently, anaphylaxis leads to 500–1,000 deaths per year (2.4 per million) in the United States, 20 deaths per year in the United Kingdom (0.33 per million), and 15 deaths per year in Australia (0.64 per million).[7] Mortality rates have decreased between the 1970s and 2000s.[44] In Australia, death from food-induced anaphylaxis occur primarily in women while deaths due to insect bites primarily occur in males.[7] Death from anaphylaxis is most commonly triggered by medications.[7]

History

The term aphylaxis was coined by Charles Richet in 1902 and later changed to anaphylaxis due to its nicer quality of speech.[16] In his experiments, Richet injected a dog with sea anemone (Actinia) toxin in an attempt to protect it. Although the dog had previously tolerated the toxin, on re-exposure with the same dose three weeks later it developed fatal anaphylaxis. Thus instead of inducing tolerance (prophylaxis), when lethal responses resulted from previously tolerated doses, he coined the word a (without) phylaxis (protection). Ana means "against" in Ancient Greek, but (as stated above) the word was changed for sound. He was subsequently awarded the Nobel Prize in Physiology or Medicine for his work on anaphylaxis in 1913.[11] The phenomenon itself, however, has been described since ancient times.[31] The term comes from the Greek words ἀνά, ana, "against", and φύλαξις, phylaxis, "protection".[45]

↑ Oswalt ML, Kemp SF (May 2007). "Anaphylaxis: office management and prevention". Immunol Allergy Clin North Am. 27 (2): 177–91, vi. doi:10.1016/j.iac.2007.03.004. PMID17493497. Clinically, anaphylaxis is considered likely to be present if any one of three criteria is satisfied within minutes to hours